title: Structure- and ligand-based drug design of novel p38-alpha MAPK inhibitors in the fight against the Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized microscopically by the presence of amyloid plaques, which are accumulations of beta-amyloid protein inter-neurons, and neurofibrillary tangles formed predominantly by highly phosphorylated forms of the microtubule-associated protein, tau, which form tangled masses that consume neuronal cell body, possibly leading to neuronal dysfunction and ultimately death. p38α mitogen-activated protein kinase (MAPK) has been implicated in both events associated with AD, tau phosphorylation and inflammation. p38α MAPK pathway is activated by a dual phosphorylation at Thr180 and Tyr182 residues. Drug design of p38α MAPK inhibitors is mainly focused on small molecules that compete for Adenosine triphosphate in the catalytic site. Here, we used different approaches of structure- and ligand-based drug design and medicinal chemistry strategies based on a selected p38α MAPK structure deposited in the Protein Data Bank in complex with inhibitor, as well as others reported in literature. As a result of the virtual screening experiments performed here, as well as molecular dynamics, molecular interaction fields studies, shape and electrostatic similarities, activity and toxicity predictions, and pharmacokinetic and physicochemical properties, we have selected 13 compounds that meet the criteria of low or no toxicity potential, good pharmacotherapeutic profile, predicted activities, and calculated values ​​comparable with those obtained for the reference compounds, while maintaining the main interactions observed for the most potent inhibitors.
authors.affiliation: a Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo , Av. do Café, s/n - Monte Alegre, Ribeirão Preto , SP 14040-903 , Brazil .
authors.forename: Flávio Roberto
authors.initials: FR
authors.lastname: Pinsetta
authors.forename: Carlton Anthony
authors.initials: CA
authors.lastname: Taft
authors.forename: Carlos Henrique Tomich
authors.initials: CH
authors.lastname: de Paula da Silva
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D062126:Databases, Chemical; D015195:Drug Design; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Alzheimer’s disease; drug design; p38 alpha MAPK